Stable parenteral formulations of duloxetine

ABSTRACT

The present invention relates to a parenteral lyophilized formulation of duloxetine or a pharmaceutically acceptable salt thereof. Further, this invention relates to duloxetine dissolved in a suitable solvent system comprising one or more buffers, stabilizers, and other pharmaceutically acceptable excipients and subsequently lyophilized. The invention also describes combination formulation of Duloxetine with other active ingredients.

FIELD OF THE INVENTION

The present invention relates to a parenteral dosage form of duloxetineor a pharmaceutically acceptable salt thereof and the method ofmanufacture of the said dosage form. The parenteral dosage form of thisinvention provides immediate relief to the patients.

BACKGROUND OF THE INVENTION

Duloxetine is a selective serotonin and norepinephrine reuptakeinhibitor (SSNRI), chemically known as(+)—N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propan-1-amine).Duloxetine is not stable in presence of acid and degrades rapidly inacidic environment of the gastrointestinal tract. One of the degradantof acid hydrolysis is 1-napthol, which is known to be toxic and causesseveral side effects. To avoid the degradation and side effects,duloxetine is supplied as an enteric coated dosage form.

Duloxetine is commercially available in USA as delayed release capsulescontaining enteric coated duloxetine hydrochloride pellets. The productis sold under the brand name Cymbalta®. Duloxetine is used in thetreatment of major depressive disorder, generalized anxiety disorder,diabetic peripheral neuropathic pain, fibromyalgia and chronicmusculoskeletal pain. The T_(lag) (time for the absorption to begin) ofduloxetine is 2 hours and Tmax (time to reach maximum concentration) is6 to 10 hours. Hence the product is indicated to be administered 2 hoursbefore the surgery for pain management.

The indications of duloxetine are such that quick onset of action isdesirable. This is not possible with the currently available entericcoated formulation where the GI transit time is more than 6 hours.Further, the capsule formulation may present difficulties in swallowingin pediatric and elderly patients. This often leads to discontinuationof treatment and poor patient compliance. There are patents describingoral formulations of duloxetine. For eg, U.S. Pat. No. 5,508,276discloses an enteric duloxetine pellet formulation comprising a) a coreconsisting of duloxetine and a pharmaceutically acceptable excipient; b)an optional separating layer; c) an enteric layer comprising hydroxylpropyl methylcellulose acetate succinate (HPMCAS) and a pharmaceuticallyacceptable excipient. The patent describes the importance of formulatingduloxetine as enteric coated pellets for better absorption andbioavailability but does not talk about parenteral formulations ofduloxetine.

U.S. Pat. No. 8,758,779 discloses duloxetine powder for oral suspensionwhereas U.S. Pat. Nos. 8,455,667 and 8,513,439 disclose oral liquidcompositions comprising duloxetine with suitable buffers. None of thesepatents have disclosures for making parenteral formulations.

The prior art formulations are associated with many disadvantages. Someof these are—increased time for absorption and onset of action for theenteric coated formulations, variability in drug absorption in differentpatients, difficulty in administering the formulations to patients whocannot take oral medication, pediatric and geriatric patients andpossible degradation of the drug due to increased time of contact withgastric acids.

Thus, there is a need to make a parenteral formulation of duloxetinethat can overcome the disadvantages associated in the prior art. Theseformulations are particularly advantageous because they result in quickaction and relief from pain because the drug enters systemic circulationdirectly bypassing first pass metabolism and gastric acid degradation.

SUMMARY OF THE INVENTION

The present invention relates to a parenteral formulation of duloxetinecomprising duloxetine dissolved in a suitable solvent system comprisingone or more buffers, stabilizers and other pharmaceutically acceptableexcipients. The formulation is in the form of a lyophilized injectioncomprising duloxetine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 01 shows Permiability of various formulations evaluated using RatIntestine at 15 minutes time (mcg/cm²).

DETAILED DESCRIPTION OF THE INVENTION

The term “duloxetine” is intended to refer to the pharmaceuticallyacceptable salts, solvates and polymorphs thereof. DuloxetineHydrochloride is most preferred.

“Water Content” in the pharmaceutical formulation plays a major role indegrading the product. Drug gets degraded when it comes in contact withwater, which ultimately effects the self-life of the product. The term“Water Content” in the present invention refers to an amount less than5% w/w and more preferably less than 3% w/w even after 6 months ofstorage at accelerated conditions.

The words “Water Content” and Moisture Content” are interchangeable andmeans the same throughout the specification.

The term “lyophilize” in the context of this invention, is intended torefer to the process of freeze drying of a solution comprisingduloxetine and other pharmaceutically acceptable excipients. The term“lyophilizate” refers to the product of lyophilization. The term“reconstitution” refers to dissolution of the lyophilizate for achievinga solution.

The inventors of the present invention defined the term “parenteral”formulation, which means a pharmaceutical formulation that can beadministered through intravenous, intramuscular, subcutaneous,intraperitoneal and intrathecal routes of administration.

In one aspect, the present invention relates to a parenteral formulationof duloxetine for preoperative, peri-operative, post-operative painmanagement to reduce or alleviate need for Opioids and, therefore,opioid-related adverse effects or opioid-induced hyperalgesia, and formanagement of chronic and acute painful conditions.

The present inventors have now surprisingly found that it is possible tomake a duloxetine lyophilized formulation that would overcome thedisadvantages associated with prior art.

In one embodiment, the invention encompasses a lyophilized parenteralformulation of duloxetine.

Lyophilization or freeze-drying is a method for dehydrating samples usedto preserve or increase stability or to stop degradation. Due to the lowwater content of lyophilized products, the action of microorganisms andenzymes is inhibited and the product life thereby increased. Inlyophilization, the sample to be lyophilized is dissolved in an aqueoussolution and subsequently frozen after which the surrounding pressure isreduced. The sample is then submitted to sublimation, optionally by theapplication of heat, in order to sublime the frozen water directly fromthe solid phase to the gas phase.

The lyophilized parenteral formulation of this invention comprisesduloxetine dissolved in an aqueous vehicle and subsequently lyophilizedin appropriate containers or glass vials. The lyophilizate thus formedcan be reconstituted with a normal physiological solution like normalsaline or with a specific diluent. The aqueous vehicle is preferably asterile aqueous vehicle that is normally used as liquid vehicle forinjection. Suitable aqueous vehicles include, for example, sterile waterand sterile aqueous vehicles that contain suitable excipients thatpromote and preserve the stability of duloxetine after reconstitution.

In another embodiment, the invention relates to a lyophilizedformulation comprising (i) duloxetine (ii) a bulking agent, (iii) anaqueous vehicle and (iv) other pharmaceutically acceptable excipients.

Bulking agents are used in lyophilization to increase product mass,adjust tonicity, improve product appearance, prevent product collapse,or aid in rehydration. Bulking agents for the purpose of this inventionmay be selected from mannitol, dextrose, cyclodextrin, sodium chloride,sorbitol and the like. Mannitol is the most preferred. The bulkingagents may make up 1-99% by weight of the lyophilized solid.

The aqueous vehicle can be selected from one or more of buffers selectedfrom the group comprising acetate buffer, phosphate buffer, asparticacid and boric acid buffer, citrate buffer and glycine buffer, succinatebuffer, alanine buffer, valine buffer, histidine buffer, lactic acidbuffer and the like. The aqueous vehicle can also contain mixture ofprocess aid solvents like alcohols, acetonitrile, acetone and like thatare removed during lyophilization.

The inventors carried out solubility/solution stability studies todetermine the solution solubility of duloxetine in various buffers atdifferent pH values. The concentration of the solution was kept at 10mg/ml,

TABLE 1 Solubility data of duloxetine in various buffers at various pHBuffer pH Observation Buffer pH Observation Phosphate 4.5 Clear solutionSerine buffer 4.5 Clear solution buffer Sodium 4.5 Clear solution 5.5Clear solution phosphate buffer Acetate 4.5 Clear solution 6.4 Clearsolution buffer 5.5 Clear solution Lactic acid 4.5 Clear solution 6.4Clear solution buffer 5.5 Clear solution 7.5 Clear solution 6.4 Clearsolution Aspartic acid 4.5 Clear solution 7.5 Clear solution and Boric5.5 Clear solution Phosphate 5.5 Insoluble acid buffer buffer Succinate4.5 Clear solution 6.4 Insoluble buffer Glycine 4.5 Clear solutionSodium 5.5 Insoluble buffer 5.5 Clear solution phosphate 6.4 Insolublebuffer 6.4 Clear solution Citrate 4.5 Insoluble 7.5 Clear solutionbuffer 5.5 Insoluble Alanine 4.5 Clear solution 6.4 Insoluble buffer 5.5Clear solution Aspartic acid 6.4 Insoluble and Boric acid buffer Valinebuffer 4.5 Clear solution Succinate 5.5 Insoluble 5.5 Clear solutionbuffer 6.4 Insoluble 6.4 Clear solution Tris buffer 4.5 Insoluble 7.5Clear solution 5.5 Insoluble Leucine 4.5 Clear solution 6.4 Insolublebuffer 5.5 Clear solution Alanine 6.4 Insoluble buffer 6.4 Clearsolution Phenyl 6.4 Insoluble alanine buffer 7.5 Clear solution Lysine4.5 Insoluble Isoleucine 4.5 Clear solution buffer 5.5 Insoluble buffer5.5 Clear solution 6.4 Insoluble 6.4 Clear solution Histidine 4.5Insoluble 7.5 Clear solution buffer 5.5 Insoluble Methionine 4.5 Clearsolution 6.4 Insoluble buffer 5.5 Clear solution Tartaric acid 4.5Insoluble 6.4 Clear solution buffer 5.5 Insoluble 7.5 Clear solution 6.4Insoluble Proline buffer 4.5 Clear solution Meglumine 4.5 Insoluble 5.5Clear solution buffer 5.5 Insoluble 6.4 Clear solution 6.4 Insoluble 7.5Clear solution Serine buffer 7.5 Insoluble Phenyl alanine 4.5 Clearsolution 0.1N Sodium 4.5 Insoluble buffer 5.5 Clear solution hydroxide5.5 Insoluble Tryptophan 4.5 Clear solution buffer 6.4 Insoluble buffer5.5 Clear solution 6.4 Clear solution 7.5 Clear solution

The solution state stability of duloxetine was studied in variousbuffers for 24 hours. The data is tabulated below:

TABLE 2 Solution state stability of duloxetine in various buffers for 24hours Formulation Aspartic Aspartic acid + acid + Glycine GlycineAcetate Acetate Boric Acid Boric Acid Buffer Buffer Buffer Buffer BufferBuffer (pH-5.5) (pH-6.4) (pH-5.5) (pH-6.4) (pH-5.5) (pH-6.4)Condition-RT-25° C. I* 24 h I* 24 h I* 24 h I* 24 h I* 24 h I* 24 h pH5.59 5.5 6.23 6.35 5.32 5.4 6.38 6.1 5.8 5.7 6.6 6.5 Assay (%) 105 104.897.7 96.6 93.9 92.4 94.3 90.3 93.0 93.3 97.9 97.8 Total 0.12 0.2 0.100.18 0.14 0.2 0.1 0.1 0.3 0.5 0.3 0.5 Impurities Note: I*: Initial

The samples were stored for 24 hours and analyzed for pH, assay andtotal impurities by standard analytical procedures. The data showed thatduloxetine has satisfactory stability in all the buffers tested. Theacetate buffer at pH-5.5 and pH-6.4 and the glycine buffer at pH-5.5 andpH-6.4 showed best results in terms of assay and total impurities.

In yet another embodiment, the invention relates to a lyophilizedformulation comprising (i) duloxetine, (ii) a bulking agent, (iii) anaqueous vehicle, (iv) a stabilizer and (v) other pharmaceuticallyacceptable excipients.

In yet another embodiment, the invention relates to a lyophilizedformulation comprising (i) duloxetine, (ii) a bulking agent (iii) anaqueous vehicle, (iv) a stabilizer, (v) one or more pH adjusting agentsand (vi) other pharmaceutically acceptable excipients.

In yet another embodiment, the invention relates to a lyophilizedformulation comprising (i) duloxetine, (ii) a bulking agent (iii) anaqueous vehicle, (iv) a stabilizer, (v) one or more surfactants and (vi)other pharmaceutically acceptable excipients.

The lyophilized formulation of the present invention has less than 0.5%w/w of each of the following impurities: duloxetine 4-napthyl isomer((4-[3-(Methylamino)-1-(thiophen-2-yl)propyl]naphthalen-1-ol), alphanapthol ((Naphthalen-1-01)), duloxetine beta napthol-1-yl isomer((2-[3-(Methylamino)-1-(thiophen-2-yl)propyl]naphthalen-1-01)). Morespecifically the above said impurities are less than 0.3% w/w each, evenafter 6 months of storage under accelerated conditions.

The stabilizer in the formulation can be selected from one or more ofDOTA, DTPA, EDTA and the like. The quantity of the stabilizer can befrom 0.001% w/w to 10% w/w.

The one or more pH adjusting agents can be selected from the groupcomprising sodium hydroxide, hydrochloric acid, mineral acids,carboxylic acids and salts thereof.

The surfactants may be selected from the group comprising lecithin, soyalecithin, egg lecithin, PEG-PE, phosphatidyl choline, etc

In yet another embodiment, the invention relates to a kit comprisinglyophilized formulation of duloxetine supplied together with a diluent.The diluent supplied in the kit can be selected from water forinjection, dextrose solution, normal saline, mannitol solution, dextrosenormal saline solution (DNS), half saline solution (with a concentrationof sodium chloride at 0.45% w/v), dextrose 5%, Normal saline withArginine (pH 10.07), Ringer Lactate solution.

The lyophilized formulation of the present invention can bereconstituted with the diluent solution described above. It can beadministered directly after reconstitution or may further be dilutedwith any of the physiologically acceptable solutions at the time ofadministration.

The lyophilized samples prepared as per the invention were reconstitutedwith water and normal saline.

TABLE 3 Reconstitution studies of duloxetine lyophilized samples BatchReconstituted media Initial pH Observation 1A Water 4.55 Clear solution1B 5.56 Clear solution 1C 6.22 Clear solution 1D 4.64 Clear solution 1E 5.43 Clear solution 1F  6.11 Clear solution 1G 4.62 Clear solution  1 H5.17 Clear solution 1I  6.02 Clear solution 1A 0.9% Sodium 4.51 Clearsolution 1B chloride 5.52 Clear solution 1C 6.14 Clear solution 1D 4.63Clear solution 1E  5.43 Clear solution 1F  6.13 Clear solution 1G 4.6Slightly hazy  1 H 5.09 Clear solution 1I  6.07 Clear solution 316A 0.45% Sodium 6.12 Clear solution Chloride 316A  Dextrose 5% 5.97 Clearsolution 316A  Dextrose Normal 5.77 Clear solution Saline 316A  Normalsaline with 7.24 Clear solution Arginine (pH 10.07) 316A  Ringer Lactate6.30 Clear solution

The formulations were observed to be clear upon reconstitution withwater, 0.9% Sodium chloride, 0.45% Sodium Chloride, Dextrose 5% DextroseNormal Saline Normal saline with Arginine (pH 10.07) Ringer Lactate.

All the formulations showed satisfactory description and desired pHrange.

Manufacturing Process

The subject-matter of the present invention further relates to a processfor preparing the lyophilized formulation and the kit. The processcomprises the steps of:

(i) mixing the following components (in any suitable order): duloxetineor a pharmaceutically acceptable salt or solvates thereof; an aqueousvehicle; one or more bulking agents; optionally one or more stabilizers;and optionally one or more pH adjusting agents; to provide for anaqueous preparation, wherein duloxetine has a concentration of 1 to 20%w/v, based on the aqueous preparation;

(ii) lyophilizing the aqueous preparation to provide for the lyophilizedformulation in solid form; and optionally

(iii) preparing the diluent and filling in suitable containers or vials;and optionally

(iv) providing the lyophilized formulation and diluent in the form of akit.

The aqueous preparation may be a suspension/dispersion or solution. Thelyophilization step may be carried out in vials, blisters or in anyother larger vessel, such as stainless-steel trays or tanks, called“bulk lyophilization”.

The bulk solution prepared in step (i) was evaluated for stability. Thedata is tabulated below. Stability of bulk solution is important toensure a quality product even in the case unforeseen prolonged processtimes. Various concentrations of the drug i.e 10 mg/ml, 20 mg/ml and 30mg/ml were studied in different pH ranges. The formulations wereprepared as per the details of example 1.

Stability data of bulk solution up to 24 h.

TABLE 4A Stability of bulk solution at a concentration of 10 mg/ml B. NO1A 1B 1C Condition 24 h 24 h 24 h 24 h 24 h 24 h Initial 2-8° C. 25° C.Initial 2-8° C. 25° C. Initial 2-8° C. 25° C. Description Clear andColourless Solution Assay (%) Related substances 101.9 101.9 102.0 103.4101.4 102.0 102.4 101.9 102.4 Impurity Name % w/w Duloxetine Alcohol0.01 0.01 0.02 ND ND ND ND ND ND Duloxetine Napthol 4-yl 0.02 0.02 0.070.01 0.01 0.03 0.01 0.01 0.02 isomer Alpha Napthol 0.03 0.03 0.12 0.010.01 0.02 0.01 0.01 0.01 Duloxetine Beta napthol- 0.02 0.02 0.07 0.010.01 0.04 0.01 0.01 0.02 1-yl isomer Duloxetine Related 0.05 0.05 0.050.06 0.06 0.06 0.06 0.06 0.04 Compound-F Total Impurities (%) 0.13 0.130.33 0.09 0.09 0.15 0.09 0.09 0.09

TABLE 4B Stability of bulk solution at a concentration of 20 mg/ml B. NO1D 1E 1F Condition 24 h 24 h 24 h 24 h 24 h 24 h Initial 2-8° C. 25° C.Initial 2-8° C. 25° C. Initial 2-8° C. 25° C. Description Clear andColourless Solution Assay (%) Related substances 102.1 101.4 101.8 103.2101.2 102.1 102.7 101.2 102.0 Impurity Name % w/w Duloxetine Alcohol0.01 0.01 0.03 ND ND 0.01 ND ND ND Duloxetine Napthol 4- 0.02 0.02 0.080.01 0.01 0.04 0.01 0.01 0.02 yl isomer Alpha Napthol 0.05 0.04 0.180.02 0.02 0.05 0.01 0.01 0.01 Duloxetine Beta 0.02 0.02 0.10 0.01 0.020.05 0.01 0.01 0.03 napthol-1-yl isomer Duloxetine Related 0.06 0.060.06 0.06 0.06 0.06 0.06 0.06 0.06 Compound-F Total Impurities (%) 0.160.15 0.46 0.10 0.11 0.21 0.09 0.09 0.12

TABLE 4C Stability of bulk solution at a concentration of 30 mg/ml B. NO1G 1H 1I Condition 24 h 24 h 24 h 24 h 24 h 24 h Initial 2-8° C. 25° C.Initial 2-8° C. 25° C. Initial 2-8° C. 25° C. Description Clear andColourless Solution Assay (%) Related substances 101.4 101.7 101.9 101.6101.4 103.0 101.1 101.3 102.0 Impurity Name % w/w Duloxetine ND 0.010.03 ND ND 0.01 ND ND ND Alcohol Duloxetine 0.02 0.02 0.08 0.01 0.010.03 0.01 0.01 0.02 Napthol 4-yl isomer Alpha Napthol 0.03 0.03 0.160.01 0.01 0.05 0.01 0.01 0.02 Duloxetine Beta 0.01 0.02 0.09 0.01 0.010.04 0.01 0.01 0.03 napthol-1-yl isomer Duloxetine Related 0.06 0.060.06 0.06 0.06 0.06 0.06 0.06 0.06 Compound-F Total Impurities 0.12 0.140.42 0.09 0.09 0.19 0.09 0.09 0.13 (%)

It is evident from the data above that the stability of bulk solution issatisfactory across the pH ranges of 4.5, 5.5 and 6.4 at temperatures of2-8° c. and 25° c. There is practically no loss in the percentage ofdrug after 24 hours and no increase in impurities.

In Vitro Ex In-Vivo Permeability Study

For administration of drug through intramuscular, subcutaneous,intraperitoneal, intrathecal, inhalation, and intranasal routes ofadministration, permeability of drug from the formulation plays asignificant role. Thus various formulations were evaluated forpermeability flux rate of Duloxetine using invitro ex-vivo ratintestine.

Details of in-vitro and ex-vivo Permeation Study:

a. Experimental Setup:

1. Permeability Barrier setup (intestine preparation):

Wistar Rats of Body weight of 300 (+25) grams were selected and fastedovernight for 12 hours before sacrificing. The animals were sacrificedby cervical dislocation and intestinal segments (jejunum portion) wereisolated. The isolated intestine segments were washed with Ringerlactate solution then stored in aerated Ringer solution till usage. 20cms of intestine segment was selected to fill 2 mL of the sample. Boththe ends of the segments were tied with cotton thread ensuring noleakage from the surface and subjected for diffusion study fordetermining permeability.

2. Sample Preparation:

The formulation of examples of 8A, 16, 17, 6 and 18 were diluted to getconcentration of 5 mg/mL of duloxetine in phosphate buffer pH 6.8. 2 mLof each solution was taken in separate.

Wherein above examples contain: (Example 8A; soya lecithin), (Example16; Egg Lecithin), (Example 17: HPBCD), (Example 6: PEGPE) andDuloxetine API—(Example 18))

3. Experimental Condition and Permeability evaluation:

Diffusion study was performed by placing the intestine segments in 50 mLof oxygenated 6.8 pH phosphate buffer at 37±0.5° C. temperature underrotary shaking at 50 rpm. The intestine acts as donor chamber anddiffusion media acts as receptor chamber from which aliquot samples werecollected at predefined time points.

4. Sample Collection:

The sample were collected at 15 mins, 30 mins, 45 mins, 1 Hrs, 2 Hrs, 3Hrs, 6 Hrs, 12 Hrs, 24 Hrs and 48 Hrs. At each time point 1 mL of thesample was collected from the diffusion phase and replaced with equalvolume of phosphate buffer of temperature 37±0.5° C. temperature. Thesamples were analysed using HPLC method for Duloxetine content.

b. Data Evaluation:

The samples collected at each time point were analysed for diffused drugcontent by HPLC method. The flux rates were calculated from slope of atrend-line plotted by taking cumulative amount drug release form unitsurface area (i.e. mcg/cm2) against time (h). The flux rates werecalculated using the following equation

(1):

J=m/At  Equation (1)

Where:

J=is the Flux of compound “m” moving through a cross-sectional area “A”during time “t”

TABLE 5 Study summary Flux rate Drug conc. in the calculated Sample ID/Description of intestinal sac/ (mcg/cm²) at S. No Details sample Volume15^(th) minute Remarks 1 Duloxetine API Drug dissolved in 2 mL of 5mg/mL 16.24 Control: API in pH in pH 6.8 phosphate buffer solution (10mg of mcg/cm² 6.8 Phosphate Phosphate buffer without any Drug in Sac)Buffer excipients 2 Duloxetine Lyophilized 2 mL of 5 mg/mL 48.21Permeability formulation with duloxetine solution (10 mg of improved > 3folds Soy lecithin formulation with Soy Drug in Sac) over API in bufferlecithin 3 Duloxetine Lyophilized 2 mL of 5 mg/mL 54.04 Permeabilityformulation with duloxetine solution (10 mg of improved > 3 folds Egglecithin formulation with Drug in Sac) over API in buffer Egg lecithin 4Duloxetine Lyophilized 2 mL of 5 mg/mL 38.93 Permeability formulationwith duloxetine solution (10 mg of improved > 2 folds HPBCD formulationwith Drug in Sac) over API in buffer HPBCD 5 Duloxetine Lyophilized 2 mLof 5 mg/mL 37.80 Permeability formulation with duloxetine solution (10mg of improved > 2 folds PEG-PE formulation with Drug in Sac) over APIin buffer PEGPE

Accompanying FIG. number 1 illustrates Permeability of variousformulations evaluated using Rat Intestine at 15 minutes time (mcg/cm2).The permeability flux rate of duloxetine formulation containingLecithin's or PEG-PE or Cyclodextrin was found to be increased by 2-3folds than compared to flux rates of drug solution that does not haveany of these excipients.

Duloxetine Combination Formulations

American Pain Society guidelines on management of acute pain and ChronicNon-cancer pain suggests “multimodal analgesia” or “balanced analgesia”for the treatment of postoperative pain management. Multimodal orBalanced Analgesia includes involves the use of more than one method ormodality of controlling pain (e.g., drugs from two or more classes, drugplus nondrug treatment) to obtain additive beneficial effects, reduceside effects, or both.

Nearly 50% of the patients who visit hospitals due to pain relatedillness suffer from acute neuropathic pain, chronic neuropathic pain,post amputation pain, cancer surgeries, post traumatic limb pain andneuropathic pain due to trauma. It would be advantageous to have aparenteral formulation with a combination of another active ingredientlike paracetamol or diclofenac or the like with duloxetine that wouldaddress the treatment need in such patients. For painful phases ofchronic pain management, a short duration of parenteral product usagefor quick response s very much desired.

In yet another embodiment, the invention also encompasses an injectionformulation comprising (i) duloxetine or a pharmaceutically acceptablesalt thereof, and (ii) a second active ingredient, selected from thegroup comprising paracetamol, diclofenac, gabapentin, pregabalin,dexamethasone, lidocaine, melatonin etc.

The following Examples are intended to illustrate the present inventionand are not to be considered as limiting the scope of the invention.

Example 1

Quantity % w/v S. No Ingredients 1A 1B 1C 1D 1E 1 F 1 G 1 H 1 I 1.Duloxetine 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Hydrochloride 2.Mannitol 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 3. DOTA* 0.02 0.020.02 0.02 0.02 0.02 0.02 0.02 0.02 4. 5.0N Sodium 0.02 0.46 0.60 0.190.84 1.06 0.96 1.06 1.14 hydroxide Solution 5. Acetate buffer 84.9 84.584.3 84.7 84.1 83.92 84.02 83.9 83.8 (10 mg/mL) pH 4.5 5.5 6.4 4.5 5.56.4 4.5 5.5 6.4 *DOTA—Dodecane tetra acetic acid

Manufacturing Process

1. 80% of required quantity of vehicle for batch is taken in a vessel.

2. Duloxetine was transferred to the above vessel and dissolved bystirring at 400 rpm till the solution turned clear.

3. Mannitol was added to the above drug solution and stirred for 3minutes till the solution becomes clear.

4. To the above solution, DOTA is added and stirred well for 1 minutetill the solution turned clear.

5. The pH of the bulk solution is adjusted by using 5.0N Sodiumhydroxide solution.

6. The final volume of the above solution is adjusted with remainingquantity of water for Injection.

7. The bulk solution is filled into vials and lyophilized.

Example 2

S. No Ingredients Qty/vial (mg) Qty % w/v 1. Duloxetine Hydrochloride56.30 3.75 2. Dextrose monohydrate 50.00 3.33 3. DOTA* 0.30 0.02 4. 0.1NSodium hydroxide Solution 0.003 0.0002 5. Glycine solution (0.5 mg/mL)Q.s 1393.40 92.89 *DOTA—Dodecane tetra acetic acid

Manufacturing Process

1. 80% of required quantity of vehicle for batch is taken in a vessel.

2. Duloxetine was transferred to the above vessel and dissolved bystirring at 400 rpm till the solution turned clear.

3. Dextrose monohydrate was added to the above drug solution and stirredfor 3 minutes till the solution becomes clear.

4. To the above solution, DOTA is added and stirred well for 1 minutetill the solution turned clear.

5. The pH of the bulk solution is adjusted to 5.5 by using 0.1 N Sodiumhydroxide Solution.

6. The final volume of the above solution is adjusted with remainingquantity of water for Injection.

7. The bulk solution is filled into vials and lyophilized.

Example 3

Example 3A Example 3B Example 3C Qty/ Qty Qty/ Qty Qty/ Qty vial % Vial% vial % S. No Ingredients (mg) w/v (mg) w/v (mg) w/v 1. Duloxetine 30.04.0 60.0 4.0 90.0 4.0 Hydrochloride 2. Mannitol 60.0 8.0 120.0 8.0 180.08.0 3. DOTA* 0.15 0.02 0.3 0.02 0.45 0.02 4. 5N Sodium 6.78 0.9 13.5 0.920.3 0.9 hydroxide Solution 5. Acetate buffer Q.s to 87.08 Q.s to 87.08Q.s to 87.08 (20 mg/mL) 0.75 mL 1.5 mL 2.25 mL *DOTA—Dodecane tetraacetic acid

Manufacturing Process

1. 80% of required total batch quantity of vehicle was dispensed andtaken in a vessel.

2. Dispensed quantity of API was transferred to the above vessel anddissolved by stirring at 400 rpm till the solution turned clear.

3. Dispensed quantity of Mannitol was added to the above drug solutionand stirred for 3 minutes till the solution become clear.

4. To the above solution dispensed quantity of stabilizer (DOTA) wasadded and stirred well for 1 minute till the solution turned clear.

5. The pH of the bulk solution was adjusted to 5.5 by using 5N Sodiumhydroxide solution.

6. Final volume of the above solution was adjusted with remainingquantity of Vehicle.

The formulations were studied for stability.

Stability Study of Duloxetine Formulations

TABLE 6A Stability study of duloxetine formulation at 30 mgconcentration B. NO 3A Condition Initial 4 W-2-8° C. 4 W-25° C. 4 W-30°C. 4 W-40° C. Strength 30 mg/vial Description White Lyophilized PowderImpurity Name % w/w Duloxetine Alcohol ND ND ND ND 0.01 DuloxetineNapthol 4-yl isomer 0.01 0.01 0.01 0.01 0.03 Alpha Napthol 0.02 0.020.02 0.02 0.03 Duloxetine Beta napthol-1-yl 0.01 0.01 0.02 0.02 0.06isomer Total Impurities (%) 0.11 0.09 0.13 0.17 0.53 Assay 103.6 101.8101.9 101.3 101.9 Water Content (mg/Vial) 4.6 4.6 6.2 14.1 7.7 Note:ND—Not determined, W—Week

TABLE 6B Stability study of duloxetine formulation at 60 mgconcentration B. NO 3B Condition Initial 4 W-2-8° C. 4 W-25° C. 4 W-30°C. 4 W-40° C. Strength 60 mg/vial Description White Lyophilized PowderImpurity Name % w/w Duloxetine Alcohol ND ND ND 0.01 0.01 DuloxetineNapthol 4-yl isomer 0.01 0.01 0.01 0.03 0.10 Alpha Napthol 0.02 0.020.02 0.03 0.07 Duloxetine Beta napthol-1-yl 0.01 0.01 0.02 0.06 0.28isomer Total Impurities (%) 0.11 0.09 0.13 0.53 1.66 Assay 102.9 102.0101.9 100.6 96.8 Water Content (mg/Vial) 9.1 8.4 11.7 10.6 10.7 Note:ND—Not determined, W—Week

TABLE 6C Stability study of duloxetine formulation at 90 mgconcentration B. NO 3C Condition Initial 4 W-2-8° C. 4 W-25° C. 4 W-30°C. 4 W-40° C. Strength 90 mg/vial Description White Lyophilized PowderImpurity Name % w/w Duloxetine Alcohol ND ND ND ND 0.01 DuloxetineNapthol 4-yl isomer 0.01 0.01 0.01 0.01 0.03 Alpha Napthol 0.02 0.020.02 0.02 0.03 Duloxetine Beta napthol-1-yl 0.01 0.01 0.02 0.02 0.07isomer Total Impurities (%) 0.11 0.09 0.13 0.17 0.54 Assay 100.8 100.0101.8 99.7 101.4 Water Content (mg/Vial) 12.5 10.8 6.2 14.1 18.5 Note:ND—Not determined, W—Week

Example 4

Qty/vial Qty S. No Ingredients (mg) % w/v 1. Duloxetine Hydrochloride60.00 4.00 2. Mannitol 120.00 8.00 3. DOTA 0.30 0.02 4. Acetic acid10.00 0.67 5. 5N Sodium hydroxide Solution 3.00 0.20 6. Glycine solution(10 mg/mL) Q.s Q.s 1.5 mL 87.11

Manufacturing Process

1. 80% of required total batch quantity of glycine solution wasdispensed and taken in a vessel.

2. Dispensed quantity of API was transferred to the above vessel anddissolved by stirring at 400 rpm till the solution turned clear.

3. Dispensed quantity of Mannitol was added to the above drug solutionand stirred for 3 minutes till the solution become clear.

4. To the above solution dispensed quantity of stabilizer (DOTA/Aceticacid) was added and stirred well for 1 minute till the solution turnedclear.

5. The pH of the bulk solution was adjusted to 5.5 by using 5N Sodiumhydroxide solution.

6. The bulk solution was lyophilized after filling into vials

Example 5

Qty/vial Quantity S. No Ingredients (mg) % w/v 1. DuloxetineHydrochloride 60.00 4.00 2. Mannitol 120.00 8.00 3. DOTA 0.30 0.02 4.Acetic acid 10.00 0.67 5. 5N Sodium hydroxide Solution 3.00 0.20 6.Serine solution (10 mg/mL) Q.s 1.5 mL 87.94

Manufacturing Process

1. 80% of required total batch quantity of Serine solution was dispensedand taken in a vessel.

2. Dispensed quantity of API was transferred to the above vessel anddissolved by stirring at 400 rpm till the solution turned clear.

3. Dispensed quantity of Mannitol was added to the above drug solutionand stirred for 3 minutes till the solution become clear.

4. To the above solution dispensed quantity of stabilizer (DOTA/Aceticacid) was added and stirred well for 1 minute till the solution turnedclear.

5. The pH of the bulk solution was adjusted to 5.5 by using 5N Sodiumhydroxide solution.

6. The bulk solution was lyophilized after filling into vials.

Example 6

Qty Qty Qty S. No Ingredients (mg/mL) % w/v % w/w 1. DuloxetineHydrochloride 30.0 3 31.40 2. Mannitol 45.0 4.5 47.10 3. EDTA 0.2 0.020.20 4. Lipoid PE 18:0/18:0-PEG- 10.0 1.0 10.46 2000 5. L-Histidine Q.sto Q.s to 0.34 pH 6.0 pH 6.0 6. 1% Glycine solution Q.s to 1 mL Q.s to100% 10.46Note: pH of the formulation: 5.5-6.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid PE18:0/18:0-PEG-2000 was transferred and stirred for 15 minutes at 450 rpmto obtain a clear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 7

Qty Qty Qty S. No Ingredients (mg/mL) % w/v % w/w 1. DuloxetineHydrochloride 30.00 3 30.864 2. Mannitol 45.00 4.5 46.296 3. EDTA 0.200.02 0.2058 4. Lipoid PE 18:0/18:0-PEG- 10.00 1.00 10.288 2000 5.Di-sodium succinic acid Q.s to Q.s to 2.0576 pH 6.0 pH 6.0 6. 1% Glycinesolution Q.s to 1 mL Q.s to 100% 10.288Note: pH of the formulation: 5.5-6.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid PE18:0/18:0-PEG-2000 was transferred and stirred for 15 minutes at 450 rpmto obtain a clear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingdisodium succinic acid.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 8

Example 8A Example 8 B Qty Qty Qty Qty Qty Qty S. No Ingredients (mg/mL)% w/v % w/w (mg/mL) % w/v % w/w 1. Duloxetine 30.00 3.00 31.40 30.0 3.030.86 Hydrochloride 2. Mannitol 45.00 4.50 47.10 45.0 4.50 46.29 3. EDTA0.20 0.02 0.20 0.20 0.02 0.205 4. Soy lecithin 10.00 1.00 10.468 10.01.00 10.28 (Lipoid S 100) 5. L-Histidine 0.32 0.03 0.34 — — — 6.Disodium — — — 2.000 0.20 2.057 Succinate 7. 1% Glycine Q.s to Q.s to10.46 Q.s to Q.s to 10.28 solution 1 mL 100% 1 mL 100%Note: pH of the formulation: 5.5 to 6.5

Manufacturing Process

Example 8A Manufacturing Process:

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 8B Manufacturing Process:

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingdisodium succinate.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

The formulation made as per the composition of 8A is tested forstability. The data at the end of 6 months is tabulated below. The dataclearly shows that each individual impurity is less than 0.5% even ataccelerated conditions after 6 months.

TABLE 7 Stability data of 8A formulation. Duloxetine HydrochlorideInjection Condition Initial 6 M-2-8° C. 6 M-25° C. 6 M-30° C. 6 M-40° C.Strength 30 mg/Vial 1. Description White White White White Light Yellowlyophilized lyophilized lyophilized lyophilized color cake cake cakecake pH 6.26 6.07 5.99 5.93 5.26 Water Content NA 0.4 0.9 0.5 1.3(mg/vial) 2. Assay (%) 104.7 104.3 100.6 101.5 102.9 3. Impurity NameDuloxetine Alcohol 0.00 ND ND ND 0.01 Duloxetine 4- 0.01 0.01 0.01 0.010.01 Napthyl isomer Alpha Napthol 0.00 0.01 0.02 0.02 0.06 DuloxetineBeta 0.01 0.01 0.01 0.01 0.01 napthol-1-yl isomer 4. Total Impurities0.10 0.10 0.13 0.14 0.40 (%)

Example 9

Qty Qty Qty Qty S. No Ingredients (mg/5 mL) (mg/mL) % w/v % w/w 1.Duloxetine 30.00 6.00 0.60 8.54 Hydrochloride 2. Pregabalin 75.0 15.01.50 21.35 3. Mannitol 185 37 3.70 52.68 4. EDTA 0.20 0.04 0.004 0.05 5.Soy lecithin 10.0 2.00 0.20 2.84 (Lipoid S 100) 6. L-Histidine 0.96 0.190.019 0.27 7. 1% Glycine Q.s to Q.s To Q.s to 14.23 solution 5 mL 1 mL100%Note: pH of the formulation: 5.5-7.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of pregabalin and stirred well for 15 minutes at400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.5±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 10

Qty Qty Qty S. No Ingredients (mg/1 mL) % w/v % w/w 1. Duloxetine 30.03.0 15.34 Hydrochloride 2. Gabapentin 100.0 10.0 51.14 3. Mannitol 45.004.50 23.01 4. EDTA 0.20 0.02 0.10 5. Soy lecithin 10.00 1.00 5.11(Lipoid S 100) 6. L-Histidine 0.32 0.033 0.16 7. 1% Glycine solution Q.sto 1 mL Q.s to 100% 5.11Note: pH of the formulation: 5.5-7.0

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of gabapentin and stirred well for 15 minutes at400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.5±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 11

Example 11A Example 11B Qty Qty Qty Qty Qty Qty Qty Qty (mg/ (mg/ % %(mg/ (mg/ % % S. No Ingredients 20 mL) mL) w/v w/w 20 mL) mL) w/v w/w 1.Duloxetine 30.00 1.50 0.30 2.66 30.00 1.50 0.30 3.22 Hydrochloride 2.Dexamethasone 8.00 0.40 0.08 0.711 12.00 0.60 0.12 1.29 sodium phosphate3. Mannitol 875.00 43.75 4.37 77.74 875.00 43.75 4.37 94.10 4. EDTA 0.200.01 0.002 0.017 0.20 0.01 0.002 0.021 5. Soy lecithin 10.00 0.50 0.100.88 10.0 0.50 0.10 1.075 (Lipoid S 100) 6. L-Histidine 2.36 0.118 0.0110.20 2.59 0.12 0.012 0.27 7. 1% Glycine Q.s to Q.s. to Q.s to 17.768 Q.sto Q.s. to Q.s to 3.22 solution 20 mL 1 mL 100% 10 mL 1 mL 100%Note: pH of the formulation: 7.5-8.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of dexamethasone sodium phosphate and stirred wellfor 45 minutes at 400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 7.8±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 12

Qty Qty Qty Qty S. No Ingredients (mg/25 mL) (mg/mL) % w/v % w/w 1.Duloxetine 30.00 1.20 0.12 2.39 Hydrochloride 2. Diclofenac 37.50 1.500.15 2.99 Sodium 3. Mannitol 920.00 36.80 3.68 73.36 4. EDTA 0.20 0.010.001 0.019 5. Soy lecithin 10.00 0.40 0.04 0.79 (Lipoid S 100) 6.L-Histidine 6.24 0.24 0.024 0.49 7. 1% Glycine Q.s to Q.s. to Q.s to19.936 solution 25 mL 1 mL 100%Note: pH of the formulation: 5.5-7.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of Diclofenac Sodium and stirred well for 45minutes at 400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.5±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 13

Qty Qty Qty Qty S. No Ingredients (mg/50 mL) (mg/mL) % w/v % w/w 1.Duloxetine 30.00 0.60 0.060 1.0375 Hydrochloride 2. Paracetamol 500.0010.00 1.000 17.291 3. Mannitol 1835.00 36.70 3.670 63.46 4. EDTA 0.200.00 0.000 0.0069 5. Soy lecithin 10.00 0.20 0.020 0.346 (Lipoid S 100)6. L-Histidine 16.4 0.328 0.0328 0.567 7. 1% Glycine Q.s to Q.s. to Q.sto 100% 17.29 solution 50 mL 1 mLNote: pH of the formulation: 5.5-6.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid S100 was transferred and stirred for 15 minutes at 450 rpm to obtain aclear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of paracetamol and stirred well for 60 minutes at400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 14

Qty Qty Qty S. No Ingredients (mg/mL) % w/v (w/w) 1. Duloxetine 30.00 315.343 Hydrochloride 2. Lidocaine HCl 100.00 10 51.143 3. Mannitol 45.004.5 23.015 4. EDTA 0.20 0.02 0.1023 5. Lipoid PE 18:0/ 10.00 1.00 5.114418:0-PEG-2000 6. L-Histidine Q.s to pH 6.0 Q.s to pH 6.0 0.168 7. 1%Glycine Q.s to 1 mL Q.s to 100% 5.12 solutionNote: pH of the formulation: 5.5-6.5

Manufacturing Process

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid PE18:0/18:0-PEG-2000 was transferred and stirred for 15 minutes at 450 rpmto obtain a clear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of lidocaine hydrochloride and stirred well for 30minutes at 400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 15

Qty Qty Qty S. No Ingredients (mg/mL) % w/v % w/w 1. Duloxetine 30.00 315.21 Hydrochloride 2. Lidocaine HCl 100.0 10 50.71 3. Mannitol 45.0 4.522.8 4. EDTA 0.20 0.02 0.10 5. Lipoid PE 18:0/ 10.0 1.0 5.0718:0-PEG-2000 6. Di-sodium succinic Q.s to pH 6.0 Q.s to pH 6.0 1.01acid 7. 1% Glycine Q.s to 1 mL Q.s to 100% 5.07 solutionNote: pH of the formulation: 5.5-6.5

Manufacturing Procedure

1. Preparation of 1% Glycine solution: Required quantity of ultrapurewater was taken in a stainless steel vessel to which desired quantity ofGlycine was added to get 1% w/v solution.

2. Preparation of Bulk solution: 80% of glycine solution required wastaken in a manufacturing vessel to which dispensed quantity of Lipoid PE18:0/18:0-PEG-2000 was transferred and stirred for 15 minutes at 450 rpmto obtain a clear solution.

3. To the above solution dispensed quantity of duloxetine was added andstirred for 30 minutes at 400 rpm for obtaining a clear solution,followed by addition of Lidocaine hydrochloride and stirred well for 30minutes at 400 rpm until a clear solution is obtained.

4. Dispensed quantity of Mannitol was added to the above solution andstirred for 30 minutes at 400 rpm to get a clear solution.

5. Required quantity of EDTA was transferred to the manufacturing vesseland stirred for 15 minutes at 400 rpm to get clear solution.

6. pH of the above bulk solution was adjusted to pH 6.0±0.1 usingdisodium succinic acid.

7. Final volume of the bulk solution was adjusted to desired level withremaining amount of 1% glycine solution.

8. The bulk solution was lyophilized after filling into vials.

Example 16

Qty Qty Qty S. No Ingredients (mg/mL) % w/v % w/w 1. Duloxetine 30.003.00 31.40 Hydrochloride 2. Mannitol 45.00 4.50 47.10 3. EDTA 0.20 0.020.20 4. Egg lecithin 10.00 1.00 10.46 (Lipoid E80S) 5. L-Histidine 0.320.03 0.34 6. 1% Glycine Q.s to 1 mL Q.s to 100% 10.46 solution

Manufacturing Process

1. Preparation of 1% glycine solution: Required quantity of glycine wasdissolved in required quantity of water.

2. Preparation of Bulk solution: 80% of glycine solution required forthe batch was taken in a manufacturing vessel to which required quantityof Lipoid E80S was transferred and stirred to obtain a clear solution.

3. To the above solution required quantity of duloxetine was added andstirred to get clear solution.

4. Required quantity of Mannitol was added to the above solution andstirred to get a clear solution.

5. Required quantity of EDTA was transferred to the above solution andstirred to get clear solution.

6. pH of the above bulk solution adjusted to pH 6.0±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted with remaining amountof 1% glycine solution.

8. The bulk solution was filtered and filled into vials and were thenpartially stoppered with single slotted lyo stopper and subjected forlyophilisation.

9. After lyophilisation the vials were stoppered completely under vacuumand were sealed with aluminium tear off seals after unloading.

Example 17

Qty Qty Qty S. No Ingredients (mg/mL) % w/v % w/w 1. Duloxetine 30.003.00 31.40 Hydrochloride 2. Mannitol 45.00 4.50 47.10 3. EDTA 0.20 0.020.20 4. HPBCD 10.00 1.00 10.46 (Hydroxypropyl Beta cyclodextrin) 5.L-Histidine 0.32 0.03 0.34 6. 1% Glycine Q.s to 1 mL Q.s to 100% 10.46solution

Manufacturing Process

1. Preparation of 1% glycine Solution: Required quantity of glycine wasdissolved in required quantity of water.

2. Preparation of Bulk Solution: 80% of glycine solution required forthe batch was taken in a manufacturing vessel to which required quantityof HPBCD was transferred and stirred obtain a clear solution.

3. To the above solution required quantity of duloxetine was added andstirred to get clear solution.

4. Required quantity of Mannitol was added to the above solution andstirred to get a clear solution.

5. Required quantity of EDTA was transferred to the above solution andstirred to get clear solution.

6. pH of the above bulk solution adjusted to pH 6.0±0.1 usingL-histidine.

7. Final volume of the bulk solution was adjusted with remaining amountof 1% glycine solution.

8. The bulk solution was filtered and filled into vials and were thenpartially stoppered with single slotted lyo stopper and subjected forlyophilisation.

9. After lyophilisation the vials were stoppered completely under vacuumand were sealed with aluminium tear off seals after unloading.

Example 18: Compositions of Duloxetine API Solution Prepared inPhosphate Buffer pH 6.4 (Used as Control in the Study)

Qty Qty Qty S. No Material name (mg/mL) % w/v % w/w 1. Duloxetine 30.003.00 2.94 Hydrochloride 2. Phosphate Buffer Q.s to 1 mL Q.s to 100%97.06 pH 6.8

Manufacturing Process

1. 80% of Phosphate buffer pH 6.8 required for the batch was taken in aSS vessel.

2. Required quantity of Duloxetine API was dispensed and transferred tothe above vessel and dissolved with stirring for 10 minutes at 300 rpm.

3. Ensuring the clarity of the solution the volume was adjusted withremaining amount of Phosphate buffer.

What is claimed is:
 1. A parenteral formulation comprising lyophilizedduloxetine or a pharmaceutically acceptable salt thereof, optionallytogether with one or more pharmaceutically acceptable excipients.
 2. Theformulation of claim 1, wherein the moisture content of the lyophilizedcake is less than 5% w/w.
 3. The formulation of claim 1, wherein thecontent of Duloxetine Alcohol, Duloxetine Napthol 4-yl isomer, AlphaNapthol and Duloxetine Beta napthol-1-yl isomer individually is lessthan 0.5% w/w.
 4. The formulation of claim 1, wherein thepharmaceutically acceptable excipients are selected from the groupcomprising bulking agents, aqueous vehicle, stabilizers, andsurfactants.
 5. The formulation of claim 4, wherein the bulking agentsare selected from mannitol, dextrose, cyclodextrin, sodium chloride andsorbitol.
 6. The formulation of claim 4, wherein the aqueous vehicle isselected from one or more buffers selected from the group comprisingacetate buffer, phosphate buffer, aspartic acid and boric acid buffer,citrate buffer and glycine buffer, histidine buffer, succinate buffer,alanine buffer, valine buffer, lactic acid buffer.
 7. The formulation ofclaim 4, wherein the surfactant is selected from the group comprisinglecithin, soya lecithin, egg lecithin, PEG-PE and phosphatidyl choline.8. A kit comprising (i) a vial comprising lyophilized duloxetine,optionally with pharmaceutically acceptable excipients and (ii) a vialcomprising a diluent
 9. The kit of claim 8 wherein the diluent isselected from the group comprising water for injection, dextrosesolution, normal saline, mannitol solution, dextrose normal salinesolution, half saline solution.
 10. The kit of claim 8, wherein the pHof the reconstituted solution is between 4-8.